Gastroenterology and Endoscopy News - PRIORITY Report - Hepatology Insights - Winter 2023

Volume 1 • 2024

Hepatology Insights

LEADING THE WAY IN

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A Supplement to

REACH

BEYOND with IMFINZI + gem-cis

IMFINZI + gem-cis: Standard of care in the 1L treatment of advanced biliary tract cancers (BTCs), including cholangiocarcinoma and gallbladder cancer1-3

NCCN

CATEGORY 1,

PREFERRED

National Comprehensive Cancer Network® (NCCN®)—Category 1, Preferred Durvalumab (IMFINZI®) + gemcitabine and cisplatin is the only NCCN Category 1, preferred primary systemic therapy option for unresectable or metastatic biliary tract cancers4*†‡

*NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. † See the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for detailed recommendations, including other treatment options.4 ‡Biliary tract cancers: Gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma.4

See the full efficacy and safety data from TOPAZ-1 at IMFINZIhcp.com/BTCs 1L=first line; CI=confidence interval; gem-cis=gemcitabine-cisplatin; HR=hazard ratio; mOS=median overall survival; mPFS=median progression-free survival; NCCN=National Comprehensive Cancer Network® (NCCN®); OS=overall survival; PFS=progression-free survival; Q3W=every 3 weeks; Q4W=every 4 weeks.

Study design: TOPAZ-1 was a randomized, double-blind, placebo-controlled, multicenter, Phase III study in patients with previously untreated locally advanced or metastatic intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer. Patients who developed recurrent disease >6 months after surgery and/or completion of adjuvant therapy were eligible. Patients were randomized 1:1 to receive IMFINZI 1500 mg (n=341) or placebo (n=344) on Day 1 + gem-cis on Days 1 and 8 Q3W for up to 8 cycles followed by IMFINZI 1500 mg or placebo Q4W until disease progression or unacceptable toxicity.1,2

Indication: IMFINZI, in combination with gemcitabine and cisplatin, is indicated for the treatment of adult patients with locally advanced or metastatic biliary tract cancer (BTC).

IMPORTANT SAFETY INFORMATION There are no contraindications for IMFINZI® (durvalumab).

Immune-Mediated Adverse Reactions Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment or after discontinuation. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

O P F

The first and only FDA-approved regimen to demonstrate significant improvement in OS and PFS vs gem-cis in locally advanced or metastatic BTCs1-3 OVERALL SURVIVAL (primary endpoint)1,2

PROGRESSION-FREE SURVIVAL (secondary endpoint)1,2

20% REDUCTION IN THE RISK

25% REDUCTION IN THE RISK

OF DEATH

OF DISEASE PROGRESSION OR DEATH

with IMFINZI + gem-cis vs gem-cis HR=0.80 (95% CI, 0.66-0.97); P=0.021§

with IMFINZI + gem-cis vs gem-cis HR=0.75 (95% CI, 0.63-0.89); P=0.001§

12.8-month mOS

VS

11.5-month mOS

(95% CI, 11.1-14.0)

7.2-month mPFS

(95% CI, 10.1-12.5)

5.7-month mPFS

VS

(95% CI, 6.7-7.4)

(95% CI, 5.6-6.7)

Data cutoff was August 11, 2021. Because superior OS was demonstrated at the prespecified interim analysis, PFS was formally evaluated at this time. Median duration of follow-up was 16.8 months (95% CI, 14.8-17.7) with IMFINZI + gem-cis and 15.9 months (95% CI, 14.9-16.9) with gem-cis.1,2 HR based on Cox proportional hazards model stratified by disease status and primary tumor location. 2-sided P value based on a stratified log-rank test compared with alpha boundary of 0.030 for OS and 0.048 for PFS.1

§

UPDATED OVERALL SURVIVAL WITH 6.5 MONTHS OF ADDITIONAL FOLLOW-UP5 2-YEAR OS RATE 12 months

1.0

24% REDUCTION IN THE RISK

The updated OS analysis was not formally tested for statistical significance

Probability of OS

with IMFINZI + gem-cis vs gem-cis HR=0.76 (95% CI, 0.64-0.91)

54.3% 47.1 %

(95% CI, 48.8-59.4)

0.8

OF DEATH

23.6%

of patients were alive at 2 years with IMFINZI + gem-cis (95% CI, 18.7-28.9)

18 months

34.8 24.1%

%

(95% CI, 41.7-52.3)

24 months

(95% CI, 29.6-40.0)

0.6

11.5%

23.6% 11.5%

of patients were alive at 2 years with gem-cis (95% CI, 7.6-16.2)

(95% CI, 18.7-28.9)

(95% CI, 19.6-28.9)

0.4

(95% CI, 7.6-16.2)

0.2

12.9-month mOS (95% CI, 11.6-14.1)

IMFINZI + gem-cis (n=341) Placebo + gem-cis (n=344)

0 0

3

6

9

12

15

18

21

24

27

30

33

Time from randomization (months) Number of patients at risk

11.3-month mOS (95% CI, 10.1-12.5)

IMFINZI + 341 331 324 309 294 278 268 252 240 227 208 194 184 169 152 134 117 96 88 74 61 52 47 44 36 33 27 21 17 10 8 gem-cis

5

3

1

Placebo + 344 337 329 316 298 282 260 241 222 198 187 175 158 138 125 104 92 76 65 53 47 37 29 21 14 11 9 gem-cis

2

1

0 0

5

3

3

3

0

Data cutoff was February 25, 2022. At the updated OS analysis, 527 events (248 in the IMFINZI group and 279 in the placebo group) had occurred. OS maturity was 77% OS rates at 12, 18, and 24 months were descriptive endpoints and were not formally tested for statistical significance Median duration of follow-up was 23.4 months (95% CI, 20.6-25.2) with IMFINZI + gem-cis and 22.4 months (95% CI, 21.4-23.8) with gem-cis.

Grades 3-4 adverse reactions were 75.7% with IMFINZI + gem-cis and 77.8% with gem-cis2 Serious adverse reactions occurred in 47% of patients receiving IMFINZI + gem-cis. The most frequent serious adverse events ( 2% of patients) were cholangitis (7%), pyrexia (3.8%), anemia (3.6%), sepsis (3.3%), and acute kidney injury (2.4%)1 Fatal adverse reactions occurred in 3.6% of patients receiving IMFINZI + gem-cis. These include ischemic or hemorrhagic stroke (4 patients), sepsis (2 patients), and upper gastrointestinal hemorrhage (2 patients)1 The most common adverse reactions (occurring in 20% of patients) with IMFINZI + gem-cis were fatigue (42%), nausea (40%), constipation (32%), decreased appetite (26%), abdominal pain (24%), rash (23%), and pyrexia (20%)1

IMPORTANT SAFETY INFORMATION (continued) Immune-Mediated Adverse Reactions (continued) Withhold or permanently discontinue IMFINZI depending on severity. See USPI Dosing and Administration for specific details.

In general, if IMFINZI requires interruption or discontinuation, administer systemic corticosteroid therapy (1 mg to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis IMFINZI can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients who did not receive recent prior radiation, the incidence of immune-mediated pneumonitis was 2.4% (34/1414), including fatal (<0.1%), and Grade 3-4 (0.4%) adverse reactions.

Please see additional Important Safety Information throughout and Brief Summary of Full Prescribing Information for IMFINZI on adjacent pages.

IMPORTANT SAFETY INFORMATION (continued) Immune-Mediated Pneumonitis (continued) In patients who received recent prior radiation, the incidence of pneumonitis (including radiation pneumonitis) in patients with unresectable Stage III NSCLC following definitive chemoradiation within 42 days prior to initiation of IMFINZI in PACIFIC was 18.3% (87/475) in patients receiving IMFINZI and 12.8% (30/234) in patients receiving placebo. Of the patients who received IMFINZI (475), 1.1% were fatal and 2.7% were Grade 3 adverse reactions. The frequency and severity of immune-mediated pneumonitis in patients who did not receive definitive chemoradiation prior to IMFINZI were similar in patients who received IMFINZI as a single agent or with ES-SCLC or BTC when given in combination with chemotherapy.

Immune-Mediated Colitis IMFINZI can cause immune-mediated colitis that is frequently associated with diarrhea. Cytomegalovirus (CMV) infection/ reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroidrefractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 2% (37/1889) of patients receiving IMFINZI, including Grade 4 (<0.1%) and Grade 3 (0.4%) adverse reactions.

Immune-Mediated Hepatitis IMFINZI can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 2.8% (52/1889) of patients receiving IMFINZI, including fatal (0.2%), Grade 4 (0.3%) and Grade 3 (1.4%) adverse reactions.

Immune-Mediated Endocrinopathies • Adrenal Insufficiency: IMFINZI can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Immune-mediated adrenal insufficiency occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions.

• Hypophysitis: IMFINZI can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement as clinically indicated. Grade 3 hypophysitis/hypopituitarism occurred in <0.1% (1/1889) of patients who received IMFINZI. • Thyroid Disorders: IMFINZI can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement therapy for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated.

• Thyroiditis: Immune-mediated thyroiditis occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions.

• Hyperthyroidism: Immune-mediated hyperthyroidism occurred in 2.1% (39/1889) of patients receiving IMFINZI. • Hypothyroidism: Immune-mediated hypothyroidism occurred in 8.3% (156/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions.

• Type 1 Diabetes Mellitus, which can present with diabetic ketoacidosis: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Grade 3 immune-mediated Type 1 diabetes mellitus occurred in <0.1% (1/1889) of patients receiving IMFINZI. Immune-Mediated Nephritis with Renal Dysfunction IMFINZI can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.5% (10/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions.

Immune-Mediated Dermatology Reactions IMFINZI can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with PD-1/L-1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes.

Immune-mediated rash or dermatitis occurred in 1.8% (34/1889) of patients receiving IMFINZI, including Grade 3 (0.4%) adverse reactions.

Other Immune-Mediated Adverse Reactions The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in patients who received IMFINZI or were reported with the use of other PD-1/PD-L1 blocking antibodies.

• Cardiac/vascular: Myocarditis, pericarditis, vasculitis.

• Nervous system: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy.

• Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment to include blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.

• Gastrointestinal: Pancreatitis including increases in serum amylase and lipase levels, gastritis, duodenitis.

• Musculoskeletal and connective tissue disorders: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic.

• •

Endocrine: Hypoparathyroidism.

Other (hematologic/immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ transplant rejection.

Infusion-Related Reactions IMFINZI can cause severe or life-threatening infusion-related reactions. Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue IMFINZI based on the severity. See USPI Dosing and Administration for specific details. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses. Infusionrelated reactions occurred in 2.2% (42/1889) of patients receiving IMFINZI, including Grade 3 (0.3%) adverse reactions.

Complications of Allogeneic HSCT after IMFINZI Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/L-1 blocking antibody. Transplant-related complications include hyperacute graft-versushost-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/L-1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/L-1 blocking antibody prior to or after an allogeneic HSCT. Embryo-Fetal Toxicity Based on its mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. In females of reproductive potential, verify pregnancy status prior to initiating IMFINZI and advise them to use effective contraception during treatment with IMFINZI and for 3 months after the last dose of IMFINZI. Lactation There is no information regarding the presence of IMFINZI in human milk; however, because of the potential for adverse reactions in breastfed infants from IMFINZI, advise women not to breastfeed during treatment and for 3 months after the last dose.

Adverse Reactions • In patients with locally advanced or metastatic BTC in the TOPAZ-1 study receiving IMFINZI (n=338), the most common adverse reactions (occurring in ö20% of patients) were fatigue (42%), nausea (40%), constipation (32%), decreased appetite (26%), abdominal pain (24%), rash (23%), and pyrexia (20%).

• In patients with locally advanced or metastatic BTC in the TOPAZ-1 study receiving IMFINZI (n=338), discontinuation due to adverse reactions occurred in 6% of the patients receiving IMFINZI plus chemotherapy. Serious adverse reactions occurred in 47% of patients receiving IMFINZI plus chemotherapy. The most frequent serious adverse reactions reported in at least 2% of patients were cholangitis (7%), pyrexia (3.8%), anemia (3.6%), sepsis (3.3%) and acute kidney injury (2.4%). Fatal adverse reactions occurred in 3.6% of patients receiving IMFINZI plus chemotherapy. These include ischemic or hemorrhagic stroke (4 patients), sepsis (2 patients), and upper gastrointestinal hemorrhage (2 patients).

The safety and effectiveness of IMFINZI have not been established in pediatric patients.

Please see additional Important Safety Information throughout and Brief Summary of Full Prescribing Information for IMFINZI on adjacent pages.

You are encouraged to report the negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

IMFINZI® (durvalumab) injection, for intravenous use Initial U.S. Approval: 2017 Brief Summary of Prescribing Information For complete prescribing information consult official package insert.

INDICATIONS AND USAGE Biliary Tract Cancers IMFINZI, in combination with gemcitabine and cisplatin, is indicated for the treatment of adult patients with locally advanced or metastatic biliary tract cancer (BTC).

DOSAGE AND ADMINISTRATION Recommended Dosage The recommended dosages for IMFINZI as a single agent and IMFINZI in combination with other therapeutic agents are presented in Table 1.

Administer IMFINZI as an intravenous infusion after dilution as recommended [see Dosage and Administration (2.3) in the full Prescribing Information].

Table 1. Recommended Dosages of IMFINZI Indication Recommended IMFINZI Dosage Duration of Therapy Combination with Other Therapeutic Agents BTC Patients with a body weight of Until disease ≥ 30 kg: progression 1,500 mg in combination with or until chemotherapy* every 3 weeks unacceptable (21 days) up to 8 cycles followed toxicity by 1,500 mg every 4 weeks as a single agent Patients with a body weight of < 30 kg: 20 mg/kg in combination with chemotherapy* every 3 weeks (21 days) up to 8 cycles followed by 20 mg/kg every 4 weeks as a single agent * Administer IMFINZI prior to chemotherapy on the same day. Refer to the Prescribing Information for the agent administered in combination with IMFINZI for recommended dosage information, as appropriate.

Dosage Modifications for Adverse Reactions No dose reduction for IMFINZI is recommended. In general, withhold IMFINZI for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue IMFINZI for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids.

Dosage modifications for IMFINZI or IMFINZI in combination with tremelimumab-actl and platinum-based chemotherapy for adverse reactions that require management different from these general guidelines are summarized in Table 4.

Table 4. Recommended Dosage Modifications for Adverse Reactions Adverse Dosage Severity* Reaction Modification Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1) in the full Prescribing Information] Grade 2 Withhold† Pneumonitis Permanently Grade 3 or 4 discontinue Grade 2 Withhold† Withhold† or Grade 3 permanently Colitis discontinue‡ Permanently Grade 4 discontinue Intestinal Permanently Any grade perforation discontinue ALT or AST increases to more than 3 and up to 8 times the ULN or Withhold† Hepatitis with total bilirubin increases to more than 1.5 and up to no tumor 3 times ULN involvement of the liver ALT or AST increases to more than 8 times ULN Permanently or discontinue total bilirubin increases to more than 3 times the ULN

Table 4. Recommended Dosage Modifications for Adverse Reactions (cont’d) Adverse Dosage Severity* Reaction Modification AST or ALT is more than 1 and up to 3 times ULN at baseline and increases to more than 5 and up to 10 times ULN or Withhold† AST or ALT is more than Hepatitis 3 and up to 5 times ULN at with tumor involvement of baseline and increases to more § than 8 and up to 10 times ULN the liver AST or ALT increases to more than 10 times ULN Permanently or discontinue total bilirubin increases to more than 3 times ULN Withhold until clinically stable or permanently Endocrinopathies Grade 3 or 4 discontinue depending on severity Grade 2 or 3 increased blood Withhold† Nephritis with creatinine Renal Grade 4 increased blood Permanently Dysfunction creatinine discontinue Suspected SJS, TEN, or Withhold† Exfoliative DRESS Dermatologic Confirmed SJS, TEN, or Permanently Conditions DRESS discontinue Permanently Myocarditis Grade 2, 3, or 4 discontinue Grade 2 Withhold† Neurological Permanently Toxicities Grade 3 or 4 discontinue Other Adverse Reactions Infusion-related Interrupt or reactions [see Grade 1 or 2 slow the rate Warnings and of infusion Precautions (5.2) in the full Permanently Grade 3 or 4 Prescribing discontinue Information] ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit normal. * Based on National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. † Resume in patients with complete or partial resolution (Grade 0 to 1) after corticosteroid taper. Permanently discontinue if no complete or partial resolution within 12 weeks of initiating corticosteroids or an inability to reduce corticosteroid dose to 10 mg of prednisone or less per day (or equivalent) within 12 weeks of initiating corticosteroids. ‡ Permanently discontinue IMFINZI for Grade 3 colitis when administered as part of a tremelimumab-actl containing regimen. § If AST and ALT are less than or equal to ULN at baseline in patients with liver involvement, withhold or permanently discontinue IMFINZI based on recommendations for hepatitis with no liver involvement.

Preparation and Administration Preparation • Visually inspect drug product for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the vial if the solution is cloudy, discolored, or visible particles are observed.

• Do not shake the vial.

• Withdraw the required volume from the vial(s) of IMFINZI and transfer into an intravenous bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Mix diluted solution by gentle inversion. Do not shake the solution. The final concentration of the diluted solution should be between 1 mg/mL and 15 mg/mL. • Discard partially used or empty vials of IMFINZI. Storage of Infusion Solution • IMFINZI does not contain a preservative.

• Administer infusion solution immediately once prepared. If the infusion solution is not administered immediately and needs to be stored, the time from preparation until the completion of the infusion should not exceed: o 28 days in a refrigerator at 2°C to 8°C (36°F to 46°F) o 8 hours at room temperature up to 25°C (77°F) • Do not freeze.

• Do not shake.

Administration • Administer infusion solution intravenously over 60 minutes through an intravenous line containing a sterile, low-protein binding 0.2 or 0.22 micron in-line filter.

• Use separate infusion bags and filters for each drug product.

IMFINZI in Combination with Other Products • Administer all drug products as separate intravenous infusions.

• Do not co-administer other drugs through the same infusion line.

• For platinum-based chemotherapy, refer to Prescribing Information for administration information.

• For pemetrexed therapy, refer to Prescribing Information for administration information.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Immune-Mediated Adverse Reactions IMFINZI is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death-receptor 1 (PD-1) or the PD-ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Important immune-mediated adverse reactions listed under Warnings and Precautions may not include all possible severe and fatal immune-mediated reactions.

The incidence and severity of immune-mediated adverse reactions were similar when IMFINZI was administered as a single agent or in combination with chemotherapy or in combination with tremelimumab-actl and platinum-based chemotherapy, unless otherwise noted.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/PD-L1 blocking antibody. While immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies.

Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue IMFINZI depending on severity [see Dosage and Administration (2.2) in the full Prescribing Information]. In general, if IMFINZI requires interruption or discontinuation, administer systemic corticosteroid therapy (1 mg to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month.

Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.

Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis IMFINZI can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation.

IMFINZI as a Single Agent In Patients Who Did Not Receive Recent Prior Radiation In patients who received IMFINZI on clinical trials in which radiation therapy was generally not administered immediately prior to initiation of IMFINZI, the incidence of immune-mediated pneumonitis was 2.4% (34/1414), including fatal (< 0.1%), and Grade 3-4 (0.4%) adverse reactions. Events resolved in 19 of the 34 patients and resulted in permanent discontinuation in 5 patients. Systemic corticosteroids were required in 19 patients (19/34) with pneumonitis who did not receive chemoradiation prior to initiation of IMFINZI. In Patients Who Received Recent Prior Radiation The incidence of pneumonitis (including radiation pneumonitis) in patients with unresectable Stage III NSCLC following definitive chemoradiation within 42 days prior to initiation of IMFINZI in PACIFIC was 18.3% (87/475) in patients receiving IMFINZI and 12.8% (30/234) in patients receiving placebo. Of the patients who received IMFINZI (475) 1.1% were fatal and 2.7% were Grade 3 adverse reactions. Events resolved in 50 of the 87 patients and resulted in permanent discontinuation in 27 patients.

Systemic corticosteroids were required in 64 patients (64/87) with pneumonitis who had received chemoradiation prior to initiation of IMFINZI, while 2 patients required use of infliximab with high-dose steroids.

IMFINZI® (durvalumab) injection, for intravenous use The frequency and severity of immune-mediated pneumonitis in patients who did not receive definitive chemoradiation prior to IMFINZI were similar whether IMFINZI was given as a single agent in patients with various cancers in a pooled data set or in patients with ES-SCLC or BTC when given in combination with chemotherapy.

Immune-Mediated Colitis IMFINZI can cause immune-mediated colitis that is frequently associated with diarrhea. Cytomegalovirus (CMV) infection/ reactivation has been reported in patients with corticosteroidrefractory immune-mediated colitis. In cases of corticosteroidrefractory colitis, consider repeating infectious workup to exclude alternative etiologies.

IMFINZI as a Single Agent Immune-mediated colitis occurred in 2% (37/1889) of patients receiving IMFINZI, including Grade 4 (< 0.1%) and Grade 3 (0.4%) adverse reactions. Events resolved in 27 of the 37 patients and resulted in permanent discontinuation in 8 patients. Systemic corticosteroids were required in all patients with immune-mediated colitis, while 2 patients (2/37) required other immunosuppressants (e.g., infliximab, mycophenolate).

Immune-Mediated Hepatitis IMFINZI can cause immune-mediated hepatitis.

IMFINZI as a Single Agent Immune-mediated hepatitis occurred in 2.8% (52/1889) of patients receiving IMFINZI, including fatal (0.2%), Grade 4 (0.3%) and Grade 3 (1.4%) adverse reactions. Events resolved in 21 of the 52 patients and resulted in permanent discontinuation of IMFINZI in 6 patients. Systemic corticosteroids were required in all patients with immune-mediated hepatitis, while 2 patients (2/52) required use of mycophenolate with high-dose steroids.

Immune-Mediated Endocrinopathies Adrenal Insufficiency IMFINZI can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold or permanently discontinue IMFINZI based on the severity [see Dosage and Administration (2.2) in the full Prescribing Information].

IMFINZI as a Single Agent Immune-mediated adrenal insufficiency occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 (< 0.1%) adverse reactions. Events resolved in 1 of the 9 patients and did not lead to permanent discontinuation of IMFINZI in any patients. Systemic corticosteroids were required in all patients with adrenal insufficiency; of these, the majority remained on systemic corticosteroids.

Hypophysitis IMFINZI can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement as clinically indicated. Withhold or permanently discontinue IMFINZI depending on severity [see Dosage and Administration (2.2) in the full Prescribing Information].

IMFINZI as a Single Agent Grade 3 hypophysitis/hypopituitarism occurred in < 0.1% (1/1889) of patients who received IMFINZI. Treatment with systemic corticosteroids was administered in this patient. The event did not lead to permanent discontinuation of IMFINZI. Thyroid Disorders IMFINZI can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement therapy for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or discontinue IMFINZI based on the severity [see Dosage and Administration (2.2) in the full Prescribing Information].

Thyroiditis IMFINZI as a Single Agent Immune-mediated thyroiditis occurred in 0.5% (9/1889) of patients receiving IMFINZI, including Grade 3 (< 0.1%) adverse reactions.

Events resolved in 4 of the 9 patients and resulted in permanent discontinuation in 1 patient. Systemic corticosteroids were required in 3 patients (3/9) with immune-mediated thyroiditis, while 8 patients (8/9) required endocrine therapy.

Hyperthyroidism IMFINZI as a Single Agent Immune-mediated hyperthyroidism occurred in 2.1% (39/1889) of patients receiving IMFINZI. Events resolved in 30 of the 39 patients and did not lead to permanent discontinuation of IMFINZI in any patients. Systemic corticosteroids were required in 9 patients (9/39) with immune-mediated hyperthyroidism, while 35 patients (35/39) required endocrine therapy.

Hypothyroidism IMFINZI as a Single Agent Immune-mediated hypothyroidism occurred in 8.3% (156/1889) of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse reactions. Events resolved in 31 of the 156 patients and did not lead to permanent discontinuation of IMFINZI in any patients.

Systemic corticosteroids were required in 11 patients (11/156) and the majority of patients (152/156) required long-term thyroid hormone replacement.

Type 1 Diabetes Mellitus, which can present with diabetic ketoacidosis Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated.

Withhold or permanently discontinue IMFINZI based on the severity [see Dosage and Administration (2.2) in the full Prescribing Information].

IMFINZI as a Single Agent Grade 3 immune-mediated type 1 diabetes mellitus occurred in < 0.1% (1/1889) of patients receiving IMFINZI. This patient required longterm insulin therapy and IMFINZI was permanently discontinued.

Two additional patients (0.1%, 2/1889) had events of hyperglycemia requiring insulin therapy that did not resolve at the time of reporting.

Immune-Mediated Nephritis with Renal Dysfunction IMFINZI can cause immune-mediated nephritis.

IMFINZI as a Single Agent Immune-mediated nephritis occurred in 0.5% (10/1889) of patients receiving IMFINZI, including Grade 3 (< 0.1%) adverse reactions.

Events resolved in 5 of the 10 patients and resulted in permanent discontinuation in 3 patients. Systemic corticosteroids were required in all patients with immune-mediated nephritis.

Immune-Mediated Dermatology Reactions IMFINZI can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with PD-1/L-1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes.

Withhold or permanently discontinue IMFINZI depending on severity [see Dosage and Administration (2.2) in the full Prescribing Information].

IMFINZI as a Single Agent Immune-mediated rash or dermatitis occurred in 1.8% (34/1889) of patients receiving IMFINZI, including Grade 3 (0.4%) adverse reactions. Events resolved in 19 of the 34 patients and resulted in permanent discontinuation in 2 patients. Systemic corticosteroids were required in all patients with immune-mediated rash or dermatitis.

Other Immune-Mediated Adverse Reactions The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in patients who received IMFINZI or IMFINZI in combination with tremelimumab-actl, or were reported with the use of other PD-1/PD-L1 blocking antibodies.

Cardiac/vascular: Myocarditis, pericarditis, vasculitis.

Nervous system: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy.

Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment.

Various grades of visual impairment to include blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.

Gastrointestinal: Pancreatitis including increases in serum amylase and lipase levels, gastritis, duodenitis.

Musculoskeletal and connective tissue disorders: Myositis/ polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatic.

Endocrine: Hypoparathyroidism.

Other (hematologic/immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ transplant rejection.

Infusion-Related Reactions IMFINZI can cause severe or life-threatening infusion-related reactions.

Monitor for signs and symptoms of infusion-related reactions.

Interrupt, slow the rate of, or permanently discontinue IMFINZI based on the severity [see Dosage and Administration (2.2) in the full Prescribing Information]. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses.

IMFINZI as a Single Agent Infusion-related reactions occurred in 2.2% (42/1889) of patients receiving IMFINZI, including Grade 3 (0.3%) adverse reactions.

2 Complications of Allogeneic HSCT after IMFINZI Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/L-1 blocking antibody.

Transplant-related complications include hyperacute graft-versushost-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/L-1 blockade and allogeneic HSCT. Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/L-1 blocking antibody prior to or after an allogeneic HSCT. Embryo-Fetal Toxicity Based on its mechanism of action and data from animal studies, IMFINZI can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of durvalumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased premature delivery, fetal loss and premature neonatal death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IMFINZI and for 3 months after the last dose of IMFINZI [see Use in Specific Populations (8.1, 8.3) in the full Prescribing Information].

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling.

• Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1) in the full Prescribing Information].

• Infusion-Related Reactions [see Warnings and Precautions (5.2) in the full Prescribing Information].

Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described in the Warnings and Precautions section reflect exposure to IMFINZI as a single agent in a total of 1889 patients enrolled in the PACIFIC study (a randomized, placebo-controlled study that enrolled 475 patients with Stage III NSCLC), Study 1108 (an open-label, single-arm, multicohort study that enrolled 970 patients with advanced solid tumors), and an additional open-label, single-arm trial (ATLANTIC Study) that enrolled 444 patients with advanced solid tumors, including NSCLC. In these trials, IMFINZI was administered at a dose of 10 mg/kg every 2 weeks. Among the 1889 patients, 38% were exposed for 6 months or more and 18% were exposed for 12 months or more. The data also reflect exposure to IMFINZI in combination with chemotherapy in 265 patients from the CASPIAN study (a randomized, open-label study in patients with ES-SCLC), in 338 patients from the TOPAZ-1 study (a randomized, double-blind study in patients with BTC). In the CASPIAN and TOPAZ-1 studies, IMFINZI was administered at a dose of 1,500 mg every 3 or 4 weeks.

The data described in the Warnings and Precautions also reflect exposure to IMFINZI 1,500 mg in combination with tremelimumabactl 300 mg in 388 patients in HIMALAYA. In the HIMALAYA study patients received IMFINZI 1,500 mg in combination with tremelimumab-actl as a single intravenous infusion of 300 mg, followed by IMFINZI 1,500 mg every 4 weeks. The pooled safety population (N = 596) described in the Warnings and Precautions section reflect exposure to IMFINZI 1,500 mg in combination with tremelimumab-actl 75 mg and histology-based platinum chemotherapy regimens in 330 patients in POSEIDON [see Clinical Studies (14.1) in the full Prescribing Information] and 266 patients with ES-SCLC in CASPIAN who received up to four cycles of platinum-etoposide plus IMFINZI 1,500 mg with tremelimumabactl 75 mg every 3 weeks followed by IMFINZI 1,500 mg every 4 weeks (an unapproved regimen for extensive stage small cell lung cancer). Among the 596 patients, 55% were exposed to IMFINZI for 6 months or more and 24% were exposed for 12 months or more.

The data described in this section reflect exposure to IMFINZI in patients with Stage III NSCLC enrolled in the PACIFIC study, in patients with metastatic NSCLC enrolled in the POSEIDON study, in patients with ES-SCLC enrolled in the CASPIAN study, in patients with BTC enrolled in the TOPAZ-1 study and in patients with uHCC included in the HIMALAYA study.

Biliary Tract Cancer Locally advanced or metastatic BTC - TOPAZ-1 The safety of IMFINZI in combination with gemcitabine and cisplatin in locally advanced or metastatic BTC was evaluated in TOPAZ-1, a randomized, double-blind, placebo-controlled, multicenter trial. A total of 338 patients received IMFINZI 1,500 mg in combination with gemcitabine and cisplatin every 3 weeks up to 8 cycles followed by IMFINZI 1,500 mg every 4 weeks until disease

IMFINZI® (durvalumab) injection, for intravenous use progression or unacceptable toxicity. Patients with active or prior documented autoimmune or inflammatory disorders, HIV infection or other active infections, including tuberculosis or hepatitis C were ineligible [see Clinical Studies (14.3) in the full Prescribing Information].

IMFINZI was discontinued due to adverse reactions in 6% of the patients receiving IMFINZI plus chemotherapy. The most frequently reported events resulting in discontinuation were sepsis (3 patients) and ischemic stroke (2 patients). The remaining events were dispersed across system organ classes and reported in 1 patient each. Serious adverse reactions occurred in 47% of patients receiving IMFINZI plus chemotherapy. The most frequent serious adverse reactions reported in at least 2% of patients were cholangitis (7%), pyrexia (3.8%), anemia (3.6%), sepsis (3.3%) and acute kidney injury (2.4%). Fatal adverse reactions occurred in 3.6% of patients receiving IMFINZI plus chemotherapy. These include ischemic or hemorrhagic stroke (4 patients), sepsis (2 patients) and upper gastrointestinal hemorrhage (2 patients). The most common adverse reactions (occurring in ≥ 20% of patients) were fatigue, nausea, constipation, decreased appetite, abdominal pain, rash and pyrexia. Table 11 summarizes the adverse reactions that occurred in patients treated with IMFINZI plus chemotherapy.

Table 11. Adverse Reactions Occurring in ≥ 10% of Patients in the TOPAZ-1 Study IMFINZI with Gemcitabine Placebo with Gemcitabine and Cisplatin and Cisplatin N = 338 N = 342 Adverse All Grades* Grade* 3-4 All Grades* Grade* 3-4 Reaction (%) (%) (%) (%) General disorders and administration site conditions Fatigue† 42 6 43 6 Pyrexia 20 1.5 16 0.6 Gastrointestinal disorders Nausea 40 1.5 34 1.8 Constipation 32 0.6 29 0.3 24 0.6 23 2.9 Abdominal pain‡ Vomiting 18 1.5 18 2.0 Diarrhea 17 1.2 15 1.8 Metabolism and nutrition disorders Decreased 26 2.1 23 0.9 appetite Skin and subcutaneous tissue disorders Rash§ 23 0.9 14 0 Pruritus 11 0 8 0 Psychiatric disorders Insomnia 10 0 11 0 *† Graded according to NCI CTCAE version 5.0.

Includes fatigue, malaise, cancer fatigue and asthenia.

Includes abdominal pain, abdominal pain lower, abdominal pain upper and flank pain. § Includes rash macular, rash maculopapular, rash morbilliform, rash papular, rash pruritic, rash pustular, rash erythematous, dermatitis acneiform, dermatitis bullous, drug eruption, eczema, erythema, dermatitis and rash. ‡

Table 12 summarizes the laboratory abnormalities in patients treated with IMFINZI plus chemotherapy.

Table 12. Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20%* of Patients in the TOPAZ-1 study

Laboratory Abnormality Chemistry Hyponatremia Gamma-glutamyltransferase increased Increased bilirubin Hypokalemia Increased AST Increased ALT Blood creatinine increased Hypomagnesemia Hypoalbuminemia Hyperkalemia Increased Alkaline Phosphatase Hypocalcemia

IMFINZI with Gemcitabine and Cisplatin Grade† 3 or 4 (%)

Placebo with Gemcitabine and Cisplatin Grade† 3 or 4 (%)

18 12

13 13

10 8 8 7 5 4.5 3.6 2.1 1.8 1.8

14 4.4 8 6 2.1 2.2 2.9 2.1 3.8 2.4

Table 12. Laboratory Abnormalities Worsening from Baseline Occurring in ≥ 20%* of Patients in the TOPAZ-1 study (cont’d) IMFINZI with Placebo with Gemcitabine Gemcitabine and Cisplatin and Cisplatin Laboratory Abnormality Grade† 3 or 4 Grade† 3 or 4 (%) (%) Hematology Neutropenia 48 49 Anemia 31 28 Leukopenia 28 28 Lymphopenia 23 15 Thrombocytopenia 18 18 *† The frequency cut off is based on any grade change from baseline.

Graded according to NCI CTCAE version 5.0. Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: IMFINZI + Gem/Cis (range: 312 to 335) and Placebo + Gem/Cis (range: 319 to 341).

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action, IMFINZI can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) in the full Prescribing Information].

There are no available data on the use of IMFINZI in pregnant women.

In animal reproduction studies, administration of durvalumab to pregnant cynomolgus monkeys from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at the clinical dose of 10 mg/kg based on area under the curve (AUC), resulted in an increase in premature delivery, fetal loss, and premature neonatal death (see Data). Human immunoglobulin G1 (IgG1) is known to cross the placental barrier; therefore, durvalumab has the potential to be transmitted from the mother to the developing fetus. Apprise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data Animal Data As reported in the literature, the PD-1/PD-L1 pathway plays a central role in preserving pregnancy by maintaining maternal immune tolerance to the fetus. In mouse allogeneic pregnancy models, disruption of PD-L1 signaling was shown to result in an increase in fetal loss. The effects of durvalumab on prenatal and postnatal development were evaluated in reproduction studies in cynomolgus monkeys. Durvalumab was administered from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at a clinical dose of 10 mg/kg (based on AUC). Administration of durvalumab resulted in premature delivery, fetal loss (abortion and stillbirth), and increase in neonatal deaths. Durvalumab was detected in infant serum on postpartum Day 1, indicating the presence of placental transfer of durvalumab. Based on its mechanism of action, fetal exposure to durvalumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immunemediated disorders have been reported in PD-1 knockout mice.

Lactation Risk Summary There are no data on the presence of durvalumab in human milk, its effects on the breastfed child, or the effects on milk production.

Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to IMFINZI are unknown. Durvalumab was present in the milk of lactating cynomolgus monkeys and was associated with premature neonatal death (see Data).

Because of the potential for adverse reactions in a breastfed child, advise women not to breastfeed during treatment with IMFINZI and for 3 months after the last dose. Refer to the Prescribing Information for the agents administered in combination with IMFINZI for recommended duration to not breastfeed, as appropriate.

Data In lactating cynomolgus monkeys, durvalumab was present in breast milk at about 0.15% of maternal serum concentrations after administration of durvalumab from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at the recommended clinical dose of 10 mg/kg (based on AUC). Administration of durvalumab resulted in premature neonatal death.

Females and Males of Reproductive Potential Pregnancy testing Verify pregnancy status of females of reproductive potential prior to initiating treatment with IMFINZI.

3 Contraception Females IMFINZI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) in the full Prescribing Information]. Advise females of reproductive potential to use effective contraception during treatment with IMFINZI and for 3 months following the last dose of IMFINZI. Refer to the Prescribing Information for the agents administered in combination with IMFINZI for recommended contraception duration, as appropriate.

Pediatric Use The safety and effectiveness of IMFINZI have not been established in pediatric patients.

Geriatric Use Of the 338 patients with BTC treated with IMFINZI in combination with chemotherapy in the TOPAZ-1 study, 158 (47%) patients were 65 years or older and 38 (11%) patients were 75 years or older. No overall differences in safety or effectiveness of IMFINZI have been observed between patients 65 years of age and older and younger adult patients.

PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (see Medication Guide in the full Prescribing Information).

Immune-Mediated Adverse Reactions Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of IMFINZI [see Warnings and Precautions (5.1) in the full Prescribing Information], including: • Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath.

• Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding.

• Colitis: Advise patients to contact their healthcare provider immediately for diarrhea, blood or mucus in stools, or severe abdominal pain.

• Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism, hyperthyroidism, adrenal insufficiency, type 1 diabetes mellitus, or hypophysitis.

• Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis.

• Dermatological Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of severe dermatological reactions.

• Pancreatitis: Advise patients to contact their healthcare provider immediately for signs or symptoms of pancreatitis.

• Other Immune-Mediated Adverse Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of pancreatitis, aseptic meningitis, encephalitis, immune thrombocytopenia, myocarditis, hemolytic anemia, myositis, uveitis, keratitis, and myasthenia gravis.

Infusion-Related Reactions: • Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.2) in the full Prescribing Information].

Complications of Allogeneic HSCT: • Advise patients of potential risk of post-transplant complications [see Warnings and Precautions (5.3) in the full Prescribing Information].

Embryo-Fetal Toxicity: • Advise females of reproductive potential that IMFINZI can cause harm to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1, 8.3) in the full Prescribing Information].

• Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of IMFINZI [see Use in Specific Populations (8.3) in the full Prescribing Information].

Lactation: • Advise female patients not to breastfeed while taking IMFINZI and for 3 months after the last dose [see Warnings and Precautions (5.4) and Use in Specific Populations (8.2) in the full Prescribing Information].

Manufactured for: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 By: AstraZeneca UK Limited, 1 Francis Crick Ave. Cambridge, England CB2 0AA US License No. 2043 IMFINZI is a registered trademark of the AstraZeneca group of companies. ©AstraZeneca 2022 6/23 US-77675 7/23

2024

Hepatology Insights Volume 1 • 2024

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Hepatology Insights

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2024

Hepatology Insights

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Real-World Data Used to Describe MASH Natural History

16

Combination of Noninvasive Tests Identifies Later-Stage Fibrosis in MASH

18

Improved Biomarkers Can Aid HCC Diagnosis, Predict Disease Course

20

First-Degree Relatives of MASLD Patients Are at Higher Risk for HCC

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A Stepwise Approach to Patients With Abnormal Liver Enzymes

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Study Underscores Need to Evaluate For Liver Disease in Patients With C. diff

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Easing ALP Cutoffs Could Allow More With PBC to Benefit From Newer Therapies

34

Disappointing Results for U.S. Hepatitis C Clearance Cascade

10

Hepatology Insights

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2024

Real-World Data Used to Describe MASH Natural History

A

longitudinal study of U.S. adults with metabolic-associated steatohepatitis

elucidates rates of and risk factors for progression to cirrhosis and further decompensation or death. The researchers expect these insights to help investigators improve trial protocols to better evaluate therapies for MASH.

12

Hepatology Insights

The team evaluated a subset of adults enrolled in the multicenter, longitudinal TARGET-NASH study of patients with metabolic dysfunction–associated steatotic liver disease (MAFLD) being treated in the United States. Patients with evidence of F2 or F3 MASH or cirrhotic MASH developing within the three years before enrollment were included in the analyses, whereas those with a history of liver transplant, diagnosis of hepatocellular carcinoma or less than six months of data after MASH development were excluded. The investigators collected retrospective data for three years before enrollment and prospective data for up to five years afterward.

Presenting the results at the EASL Congress

2024

2023 (abstract OS-089), the researchers, led

by Philip Newsome, MD, PhD, a professor of hepatology and the director of the Centre for Liver & GI Research at the University of Birmingham, in England, reported that at index, 703 participants had F2 or F3 MASH, 768 patients had compensated cirrhotic MASH, and 354 patients had decompensated cirrhotic MASH. The noncirrhotic MASH patients were more likely to be younger, non-white, and have a history of hyperlipidemia than the cirrhotic MASH patients. The decompensated cirrhotic MASH patients were more likely to be treated at an academic medical center than at a community medical center, and were more likely than patients with compensated cirrhotic MASH and noncirrhotic MASH to have a history of cardiovascular disease or event.

Progression to Decompensated MASH In patients with compensated MASH cirrhosis, the researchers evaluated risk for progression to decompensation depending on whether patients had clinically significant portal hypertension (CSPH) and/or varices. Compared with patients without CSPH, of whom 22% decompensated, those with CSPH and varices

‘

Clinicians can tell patients with a diagnosis of MASH that if you stop smoking, not only do you reduce your CVD risk—the leading cause of mortality in MASH—but also possibly your liver-related mortality and risk for cirrhosis.

’

Progression to Cirrhotic MASH Among the participants with F2 or F3 MASH at index, 121 (17%) progressed to cirrhotic MASH and eight died within 84 months.

When examined as a composite outcome of progression to cirrhosis or all-cause mortality, significant predictors were sex and smoking status, with female participants (hazard ratio [HR], 0.60; 95% CI, 0.40-0.91) and those who never smoked (HR, 0.46; 95% CI, 0.24-0.90) less likely to experience the outcome than male patients and those who currently smoke, respectively. Age, history of diabetes, history of cardiovascular disease, history of sleep apnea, history of opioid use and fibrosis-4 value at index were not significant predictors.

The elucidation of risk factors has important clinical implications, Lisa VanWagner, MD, MSc, the director of clinical research in the Division of Digestive and Liver Diseases at UT Southwestern Medical Center, in Dallas, told GEN Priority Report. Smoking, in particular, is “modifiable and actionable,” and clinicians can “tell patients with a diagnosis of MASH that if you stop smoking, not only do you reduce your CVD risk— the leading cause of mortality in MASH—but also possibly your liver-related mortality and risk for cirrhosis,” said Dr. VanWagner, who was not involved in the study.

—Lisa VanWagner, MD, MSc UT Southwestern Medical Center, Dallas

were significantly more likely to decompensate (HR, 2.35; 95% CI, 1.69-3.27). Those with CSPH but without varices were somewhat more likely than those without CSPH to progress also, but the extent did not reach statistical significance (HR, 1.33; 95% CI, 0.97-1.83).

Within the compensated MASH cirrhosis subgroup, the researchers also evaluated risk for the composite outcome of progression to decompensated MASH cirrhosis, liver transplant, Model for End-stage Liver Disease (MELD) score change to over 15, or death within 84 months. Overall, 28% of participants without CSPH, 32% of those with CSPH and without varices, and 49% of those with CSPH and varices experienced the composite outcome.

Individuals with CSPH and varices were more than twice as likely as those without CSPH or varices to meet the composite outcome criteria (HR, 2.06; 95% CI, 1.51-2.83). However, those with CSPH but without varices were not significantly more likely than those without CSPH or varices to experience the outcome.

Hepatology Insights

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Significant predictors of a decreased risk for the composite outcome included albumin level at index (HR, 0.49; 95% CI, 0.34-0.71), history of hypertension (HR, 0.66; 95% CI, 0.43-1.00) and hemoglobin value at index (HR, 0.88; 95% CI, 0.79-0.98). Significant predictors of an increased risk for the composite outcome included total bilirubin at index (HR, 1.42; 95% CI, 1.07-1.87) and fibrosis-4 value at index

Table. Hazard Ratios for All-Cause Mortality in Cirrhotic MASH Subgroups Versus Noncirrhotic MASH Subgroup

Hazard ratio

Mortality Risk by Severity The researchers also studied the incidence of all-cause mortality among the subgroups.

Compared with noncirrhotic MASH patients, cirrhotic MASH patients were more likely to die within the 84 months post-index. This was true for each subgroup of cirrhotic MASH patients (Table).

95% CI

Decompensated cirrhosis

15.08

7.23-31.43

Compensated cirrhosis with CSPH and varices

6.10

2.53-14.70

Compensated cirrhosis with CSPH and without varices

6.74

3.06-14.87

Compensated cirrhosis without CSPH

7.01

3.15-15.63

CSPH, clinically significant portal hypertension; MASH, metabolic-associated steatohepatitis.

(HR, 1.08; 95% CI, 1.03-1.13). Age; sex; body mass index; alcohol use; alkaline phosphatase level; and history of diabetes, hyperlipidemia, and use of statins, GLP-1 receptor agonists or nonsteroidal anti-inflammatory drugs were not significant predictors of the outcome.

The finding that a history of hypertension was protective stood out to Dr. VanWagner, given that “typically, patients with end-stage liver disease develop circulatory dysfunction including reduced systemic vascular resistance and hypotension.” She posited that “hypertension may be a marker of higher vascular tone, thus supporting the cardiovascular system.” To her, this is a “hypothesis-driving finding that deserves further attention in future studies, particularly … trials to study treatments in [MASH

14

that] may have effects on vasculature.” She noted that the liver cirrhosis network RESCU trial (ClinicalTrials.gov Identifier: NCT05832229) is examining “statins and their role in possible prevention of decompensation.”

Hepatology Insights

Applying the Findings In Practice and Research To the researchers, these findings add to the body of literature on the natural history of MASH, in a set of “patients from a broader clinical background.” Dr. VanWagner echoed the researchers’ sentiments on the value of the study, noting that “it confirms much of what we thought was true in [MASH] and [MASH] cirrhosis.” But, she added, “now we have better data to support rates that we might quote patients for risk of progression, which is helpful information for clinical monitoring and patient planning purposes.”

However, Dr. VanWagner pointed out that the “possibility for misclassification bias” introduced by “the non-histologic criteria [the study] used to define MASH and MASH cirrhosis, which does differ from most clinical trial inclusion criteria,” was a “major limitation to the study.”

Despite this limitation, Dr. VanWagner said the study’s findings can inform future study design, noting that “understanding the natural history of MASH in a real-world setting helps us to better understand trial design as we think about whether a drug alters the natural history.

It is meaningful to know that we likely need to extend our trials to at least four to five years to really see if the drug is making an impact on the natural history of the disease.”

—Natasha Albaneze, MPH

Complete archives Web-only content Multimedia And more …

2024

Combination of Noninvasive Tests Identifies Later-Stage Fibrosis in MASH

A

combination of noninvasive tests can identify patients with metabolic dysfunction–associated steatohepatitis who have stage F2 or F3 pre-cirrhotic

fibrosis, potentially easing the need for liver biopsies, according to a new study.

“We just don’t have enough providers to perform liver biopsies on the more 6 million people in this country with [MASH],” Manal Abdelmalek, MD, the director of NAFLD Clinical Research at Mayo Clinic in Rochester, Minn., told GEN Priority Report. “We’re going

‘ This approach eliminates unnecessary testing for low-risk

cases, reduces risks that serious cases might be missed, reduces the healthcare burden and can be cost-effective.’

—Rohit Loomba, MD, MHSc University of California, San Diego

to need a sequential or combination testing [approach] with at least two or more noninvasive biomarkers along with additional serum markers to accurately identify the at-risk patient with [MASH] and pre-cirrhotic fibrosis and minimize the misclassification of patients for clinical trials or therapies,” said Dr. Abdelmalek, who was not involved with the study.

Previous work has suggested that noninvasive tests (NITs) could be useful, but the new study is the first to examine them in the context of a clinical trial, according to Rohit Loomba, MD, MHSc,

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Hepatology Insights

who presented the results at EASL Congress 2023. “It is critical that individual NITs be tested in diverse cohorts, populations and settings to ensure that a clear picture of their performance and limitations is developed,” said Dr. Loomba, a professor of medicine, the chief of the Division of Gastroenterology and Hepatology and the director of the NAFLD Research Center at the University of California, San Diego.

Dr. Loomba and his co-investigators analyzed data from 6,060 patients who were screened for eligibility for the REGENERATE and REVERSE trials, which evaluated obeticholic acid for the treatment of pre-cirrhotic fibrosis in MASH patients. In the new research, they assessed whether the Enhanced Liver Fibrosis (ELF) score, the fibrosis-4 (FIB-4) score and FibroScan (Echosens) results could be combined with laboratory test results—such as direct bilirubin, albumin and platelet count—to identify patients with MASH. They compared findings from the NITs with biopsy-confirmed fibrosis stage.

The combination of FIB-4 with either ELF or FibroScan, in addition to serum markers to rule out cirrhosis, revealed pre-cirrhotic fibrosis in MASH patients with high specificity and high positive predictive value (PPV), although

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the sensitivity remained low. Nevertheless, the approach identified about one-third of patients who later had biopsy-confirmed F2/F3 fibrosis, and 38% of patients with F3 fibrosis.

Upper bound values of FIB-4 (2.7), FibroScan (18 kPa) and ELF (11.0) excluded up to 56.9% of F4 cases, and missed just 16.6% of F2/F3 cases.

When both lower and upper bounds were considered, FIB-4 (1.3-2.7), FibroScan (9.5-18 kPa) and ELF-4 (9.6-11.0) identified approximately half of F3/F4 patients but on their own did not adequately discriminate F2/F3 from F0, F1 and F4. To exclude F4 patients, the researchers identified low platelet levels (<150,000/mcL), high conjugated bilirubin (>0.5 mg/dL) and low albumin (<3.8 g/dL) as the best performers to distinguish F2/F3 from F4.

Ultimately, the best performance at distinguishing F2/F3 and excluding other stages was achieved by combining FIB-4 (1.3-2.7) and either ELF (9.6-11.0) or FibroScan (9.6-18.0 kPa), along with exclusion of low platelets, high conjugated bilirubin or low albumin. This led to a 91% specificity and 89% PPV, with the highest area under the receiver operating characteristic curve (0.75; 95% CI, 0.73-0.76).

Other NIT combinations performed nearly as well, and the researchers called for all of them to be tested against multiple independent data sets to determine the best combination.

Although the performance of the approach wasn’t perfect, Dr. Loomba said positive results could trigger intermediate or indeterminate cases to undergo more accurate and expensive diagnostic workups. “This approach eliminates unnecessary testing for low-risk cases, reduces risks that serious cases might be missed, reduces the healthcare burden and can be cost-effective,” he said.

The new research is the first to examine NITs in the context of a clinical trial. “Previous studies have suggested individual NITs can be extremely useful with high accuracy when used in concert with more accurate but more expensive tests,” Dr. Loomba said. “However,” he stressed that “it is critical that individual NITs be tested in diverse cohorts, populations and settings to ensure that a clear picture of their performance and limitations is developed.”

FIB-4 (1.3-2.7) +

ELF (9.6-11.0) or Rohit Loomba, MD, MHSc

FibroScan (9.6-18.0 kPa) + exclusion of low platelets, high conjugated bilirubin or low albumin yielded a

91% specificity and 89% PPV for distinguishing F2/F3 and excluding other stages.

ELF, Enhanced Liver Fibrosis; FIB-4, fibrosis-4; PPV, positive predictive value.

—Jim Kling Dr. Abdelmalek reported a financial relationship with Intercept and was an investigator for the REGENERATE and REVERSE trials. Dr. Loomba reported financial relationships with 89bio, Aardvark, Altimmune, Alnylam/Regeneron, Amgen, Arrowhead, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, CohBar, Galectin, Galmed, Gilead, Glympse Bio, Hanmi, HighTide, Inipharm, Intercept, Inventiva, Ionis, Janssen, Lilly, LipoNexus, Madrigal, Merck, Metacrine, NGM Bio, Novartis, Novo Nordisk, Pfizer, Sagimet, Sonic Incytes, Terns, Theratechnologies and Viking.

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Improved Biomarkers Can Aid HCC Diagnosis, Predict Disease Course

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esearchers in the Netherlands and Latin America have identified a new score

using existing serum biomarkers to detect early stages of hepatocellular carcinoma.

Timely detection is paramount, stressed researcher André Boonstra, PhD, an experimental hepatologist at Erasmus Medical Center, in Rotterdam, Netherlands. “Early detection significantly improves a patient’s chances of survival,” Dr. Boonstra said, noting that in early HCC stages, treatment with surgical resection, radiofrequency ablation and, in some cases, a

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Hepatology Insights

liver transplant, is still possible.

Alpha-fetoprotein (AFP) has shown limitations for effective identification of early-stage HCC, so hepatology researchers now advocate for the use of the GALAD score, which is a composite of biomarkers, Dr Boonstra noted. But the adoption of GALAD in clinical practice has been slower than desired, he said.

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Diverse Populations

recalculated using different patient cohorts.”

They recommended that GALAD be included “in international guidelines for HCC diagnosis and surveillance” based on their findings. In addition, they pointed to the emerging value of the new ASAP model, noting that it “has the potential to revolutionize the routine HCC surveillance and diagnosis” for cirrhotic and noncirrhotic patients as well as those with low-AFP early-stage HCC.

The research team investigated various approaches, including AFP, GALAD score and a new score they developed, to detect early-stage HCC. They used more than 3,000 blood samples collected from European and Latin American patients, underscoring that HCC has distinct etiologies that generally differ between these populations. For example, in Peru, HCC patients tend to be younger and present with a different composition of underlying liver diseases compared Diagnostic and Prognostic Roles with European patients.

In the Latin American cohort (n=288), the The EASL study reaffirms the importance of investigators found that AFP alone demon- analyzing biomarkers for liver cancer prognostrated limited ability to distinguish cirrhosis sis, said Ashwani K. Singal, MD, MS, FAGC, from HCC, but AFP combined with other bio- FAASLD, AGAF, a professor of medicine at the markers to form the GALAD score resulted in University of Louisville, in Kentucky. Biomarkers substantial improvement (area under the receiver can predict the disease course over the next five operating curve [AUC], 87.9), the team reported to 10 years, and they also can predict treatment at the EASL Congress 2023 and in Hepatology response, said Dr. Singal, who was not involved Communications (2023;7:e0264).

In the Latin American (n=581) and European (n=747) patients, the researchers also tested a novel This finding suggests that the ASAP score could be multivariate score they developed, a valuable tool for detecting HCC early. called the ASAP score, which — André Boonstra, PhD uses a patient’s age, sex and two Erasmus Medical Center, Rotterdam, Netherlands protein levels—AFP and protein induced by vitamin K absence (PIVKA-II)—as indicators.

The ASAP score exhibited good performance to differentiate HCC from cirrho- in the study. “Chemotherapy works differently sis in a combined Latin American and European in HCC patients, and there is an unmet need cohort (744 HCC, 584 cirrhosis), with an AUC for personalized medicine and to use a specific of 0.85 for overall HCC and 0.82 for early-stage chemotherapy target in each patient to maximize HCC.In addition, the ASAP model differen- benefit,” Dr. Singal said. In this regard, painstiated cirrhosis (n=213) from pre-diagnostic taking biomarker detection will be of utmost HCC (n=88) in those who would develop HCC importance to solve these clinical conundrums, in in an average of 13 months, with a sensitivity he added. of 49% and a specificity of 90% (P<0.0001).

Dr. Singal suggested that beyond a prognostic “This finding suggests that the ASAP score role, an accurate biomarker also can be very usecould be a valuable tool for detecting HCC ful in early detection of liver cancer when comearly,” Dr. Boonstra said, when patients are more bined with ultrasound surveillance. likely to respond favorably to treatment.

—Marcus A. Banks The researchers concluded that “the GALAD The study was an investigator-initiated study that was partly supported financially or in kind by model has proven to be robust in early-stage Fujirebio Europe and Fujifilm. Dr. Singal reported no HCC and diverse patient populations, and its relevant financial disclosures. He is a member of the performance remains consistent even when Gastroenterology & Endoscopy News editorial board.

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First-Degree Relatives of MASLD Patients Are at Higher Risk for HCC

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irst-degree relatives of people with metabolic dysfunction–associated steatotic liver disease

are at higher risk for developing hepatocellular carcinoma, according to a longitudinal study.

This is especially true if those with MASLD have advanced fibrosis or cirrhosis.

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Hepatology Insights

“There was this notion that [MASLD] has a high degree of heritability and, therefore, firstdegree relatives were at greater risk, but no longterm study had been performed,” said investigator Fahim Ebrahimi, MD, MSc, a gastroenterologist and researcher in the Department of Medical Epidemiology and Biostatistics at the Karolinska Institutet, in Stockholm.

Using data from the Swedish Total Population Register, Dr. Ebrahimi and his co-investigators analyzed the health outcomes of first-degree relatives and spouses of people with biopsy-proven MASLD from 1966 to 2017. This comprised 11,924 people with MASLD, 48,032 first-degree relatives and 9,406 spouses. The researchers compared their health outcomes with those of firstdegree relatives and spouses of matched general population comparators without a diagnosis of MASLD.

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Compared with first-degree relatives of people without MASLD (n=197,303), relatives of people with MASLD (n=38,018) developed more cases of HCC over a median follow-up period of 17 years: 85 (0.2%) versus 272 HCC diagnoses (0.1%), the researchers reported at the EASL Congress 2023 and in the Journal of Hepatology (2023 Aug 28. https://doi.org/10.1016/j. jhep.2023.08.018).

“Over a lifetime the absolute risk is not so high. So, our findings were a bit reassuring,” Dr. Ebrahimi said. But subgroup analyses revealed that first-degree relatives of people with advanced fibrosis or cirrhosis had a twofold higher risk for developing HCC than relatives of people with simple steatosis or metabolic dysfunction–associated steatohepatitis without fibrosis (adjusted hazard ratio, 2.14; 95% CI, 1.07-4.27).

Spouses of people with a diagnosis of MASLD did not have a statistically significant difference in HCC risk than spouses of those without MASLD. However, the spouses of patients with MASLD were at a higher relative risk for developing cirrhosis.

Targeted Screening To Uncover More MASH “There’s always this balancing between screening costs and actual risks,” Dr. Ebrahimi told GEN Priority Report, noting that a general nationwide screening program for HCC would be too expensive and isn’t warranted by these data anyway. However, first-degree relatives of people with advanced fibrosis or cirrhosis may indeed benefit from screening to determine whether they have MASLD or advanced fibrosis that could predispose to liver cancer, he said.

“This is good information to motivate us to screen for fatty liver and fibrosis more intentionally,” Nadege Gunn, MD, told GEN Priority Report. “We don’t need to go so far as to screen everybody for cancer outright without evidence of fibrosis or advanced disease, but we should be trying to uncover more and more metabolicdysfunction-associated steatotic liver disease,” said Dr. Gunn, a gastroenterologist and hepatologist who serves as the medical director and president of the Impact Research Institute, in Waco, Texas.

Dr. Gunn recommended that primary care physicians and gastroenterologists use the Enhanced Liver Fibrosis (ELF, Siemens) test as a noninvasive tool to assess whether a patient with MASLD has advanced fibrosis or cirrhosis.

The FDA approved the use of the ELF test in July 2023, which Dr. Gunn said she hopes will make fibrosis detection without a biopsy more common. In addition to those tools, Dr. Gunn touted the benefits of using ultrasound vibrationcontrolled transient elastography or FibroScan (Echosens) technology.

‘ This is good information to motivate us to screen for fatty liver and fibrosis more intentionally.’

—Nadege Gunn, MD Impact Research Institute, Waco, Texas

“Elastography really changed the game; it has been pivotal” as a way to measure a patient’s severity of scarring, which is a risk factor that could lead to cancer, Dr. Gunn said. She noted that practicing gastroenterologists may need guidance in how to interpret various elastography results because the technology is still evolving.

Once someone has fatty liver disease, Dr. Gunn noted that diet and lifestyle modifications remain the mainstays of treatment so that the liver disease does not worsen. Glucagon-like peptide-1 (GLP-1) inhibitors, such as semaglutide, are now another option, Dr. Gunn added, as gastroenterologists wait for FDA approval of a drug targeting MASLD/MASH. In addition, she said, work still needs to be done to identify best-in-class prognostic biomarkers for the severity of the fatty liver disease course. Noting that “the ELF score can tell us that” at later stages, Dr. Gunn said, “it would be nice to know this information much earlier, and save some people from having to get a liver transplant.”

—Marcus A. Banks Drs. Ebrahimi and Gunn reported no relevant financial disclosures.

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A Stepwise Approach to Patients With Abnormal Liver Enzymes STANLEY MARTIN COHEN, MD, FAASLD, FACG Medical Director of Hepatology University Hospitals Cleveland Medical Center Professor of Medicine Case Western Reserve University School of Medicine Cleveland, Ohio

bnormal liver tests are a common occurrence in the United States.1 Based on National Health and Nutrition Examination Survey III data, approximately 7.9% of the population has an elevated level of aspartate aminotransferase (AST) or alanine aminotransferase (ALT).2 Because of this, abnormal liver tests are a common indication for referral to a gastroenterologist. This article outlines a stepwise, guideline-based approach to management of these patients.

A

The terms “liver function tests,” or “LFTs,” are not exactly correct. Although some liver tests—such as bilirubin, albumin, and international normalized ratio—do relate to liver function, liver tests such as AST, ALT, and alkaline phosphatase relate more to liver injury and/or other structural issues. For this reason, this article uses the terms abnormal liver chemistries, tests, or enzymes and specifically focuses on the evaluation of patients with abnormal ALT, AST, alkaline phosphatase, and/or bilirubin.

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AST and ALT Assessing a patient with abnormal AST and ALT requires delving further into the definition of normal versus abnormal. Normal lab values generally are defined as the mean value of a healthy population ± 2 SD, which is based on the control population that the various labs use.

Upper limit of normal (ULN) levels for AST and ALT can vary by a factor of 2 to 4, depending on the lab.

Studies have demonstrated that individuals with higher AST and ALT have increased morbidity and/or mortality,3-6 which likely represents underlying fatty liver disease and its associated metabolic risk factors as well as alcoholic liver disease. Some of the control populations used by labs to determine their specific ULN values have included individuals with these risk factors.

Because of this, many have proposed the concept of a true normal AST and ALT level based on a control population that excludes patients with fatty liver risk factors and alcohol use, which would result in much lower ULN levels for AST and ALT. In the 2017 clinical guideline on abnormal liver chemistries from American College of Gastroenterology (ACG), based on many studies and surveys of many of the world’s leading hepatologists, we proposed that the true ULN for ALT should be 29 to 33 U/L in males and 19 to 25 U/L in females.7 However, using these lower ALT ULN values will significantly increase the number of patients defined as having elevated liver enzymes, up to 36% of men and 28% of women.8 This has clinical and financial implications, including more patients being referred for elevated liver enzymes, more testing, and increased costs.

AST and ALT are preformed in liver cells and released as a result of hepatocellular injury.

However, AST also is found in skeletal muscle, cardiac muscle, the kidneys, and the brain. ALT is present mostly in the liver and, thus, is a more specific marker of liver injury than AST. There are no specific clarifying tests to determine whether AST or ALT elevations are from the liver.

Alkaline Phosphatase Alkaline phosphatase is found in the hepatocytes on the canalicular membrane. It increases

in patients with cholestatic liver disease, due to either mechanical obstruction (eg, extrahepatic cholestasis) or impairment of bile formation/ flow/filtration by the liver (eg, intrahepatic cholestasis). Hepatic elevations of alkaline phosphatase can occur in obstructive liver diseases, infiltrative liver diseases, primary cholestatic diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), and

Table 1. Patterns of AST and ALT In Liver Disease AST > ALT • • • • • • •

Alcoholic liver disease Budd-Chiari syndrome Cardiac disease Cirrhosis Congestive hepatopathy Ischemic hepatitis/shock liver Muscle disease

ALT > AST • • • • • • • • •

Alpha-1 antitrypsin deficiency Autoimmune hepatitis Drug-induced liver injury Fatty liver disease Hemochromatosis Toxic hepatitis Pregnancy-related liver Viral hepatitis Wilson’s disease

ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Table 2. Magnitude of AST and ALT

Elevations in Liver Disease Type of liver disease

AST/ALT elevation, IU/L

Alcoholic liver disease

Usually <200-300

Atypical viral hepatitis such as severe herpes hepatitis

Any level, even >10,000

Autoimmune hepatitis Classic acute viral hepatitis A, B, C

Up to 3,000-5,000

Complete biliary obstruction

Up to 1,000

Fatty liver disease/NASH

Usually <200-300

Shock liver/ischemic hepatitis

Any level, even >10,000

Toxic hepatitis ALT, alanine aminotransferase; AST, aspartate aminotransferase; NASH, nonalcoholic steatohepatitis.

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granulomatous liver diseases. Alkaline phosphatase also is found in other organs including bone (the most common extrahepatic source), the placenta, the intestines, and the kidneys.

The most common clarifying test used is a gamma-glutamyl transferase (GGT). However, GGT can be elevated in patients with significant alcohol use, even in the absence of liver disease.

Alkaline phosphatase isoenzymes also can be used as a clarifying test and can point to the specific origin of the elevation.

Bilirubin Bilirubin is a breakdown product of senescent red blood cells and generally circulates in the unconjugated form tightly bound to albumin.

Conjugation of bilirubin makes it water-soluble,

History and physical exam to assess for: • Alcohol use • Fatty liver risk factors • Potentially hepatotoxic medications • Viral hepatitis risk factors

If cause not found, perform the following tests: • CBC • Hepatic function panel • Hepatitis B surface antibody • Hepatitis B surface antigen • Hepatitis C antibody • Iron panel and ferritin • Ultrasound

If still elevated, complete the full serological workup to include autoimmune and metabolic/genetic serologies.

If above is unrevealing, work on NASH risk factors and alcohol avoidance and repeat liver tests in 3 mo (if mild) or 6 mo (if borderline).

If above testing is unrevealing and ALT still elevated, consider referral to liver specialist and/or liver biopsy.

Figure 1. Borderline-mild ALT elevation (<2-5 x ULN).

CBC, complete blood count; NASH, nonalcoholic steatohepatitis; ULN, upper limit of normal.

Adapted from reference 7.

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allowing it to be excreted in the bile and converted in the colon to urobilinogen, which is excreted in urine and stool.

The main clarifying test for bilirubin elevation would be fractionation of the bilirubin.

Fractionating the bilirubin may not be necessary in patients who present with obvious liver disease, including elevated AST, ALT, and/or alkaline phosphatase.

Elevated conjugated (direct) bilirubin occurs with liver disease and/or cholestasis, and should prompt a liver workup. Potential etiologies include biliary obstruction, acute alcoholic hepatitis, postoperative jaundice, drug-induced liver injury, hepatitis, and multifactorial/ICU jaundice. Elevated unconjugated (indirect) bilirubin can be seen in conditions such as Gilbert’s syndrome (about 6% of the US population)9 or hemolysis and should prompt an initial assessment for nonhepatic causes.

Algorithmic Approach to Diagnosis In Setting of Elevated Liver Enzymes Unless there is obvious evidence of liver damage, clinicians may want to start with repeat liver tests to confirm elevations. Clinicians then should consider several factors, including ruling out nonhepatic causes of elevations, assessing the various common/uncommon causes of elevated liver enzymes, defining the pattern of elevations, assessing the magnitude of elevations, and looking into the timing of the elevations.

The first step should be a thorough history and physical examination to assess for fatty liver disease risk factors, alcohol use, risk factors for autoimmune diseases, family history of liver disease, and a thorough evaluation of the patient’s medication history. Drug-induced liver injury can be precipitated by prescription medications, herbal supplements, and over-the-counter agents.

Getting an accurate history of these potential agents can be very difficult. On exam, clinicians should look for obesity, stigmata of chronic liver disease, and any specific clues that may be related to liver disease, such as Kayser-Fleischer rings seen in Wilson’s disease. They also should make a quick assessment to ensure there is no evidence of liver failure, such as the development of coagulopathy and encephalopathy, because the workup is very different in that case and may require an

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History, physical exam, and assessment as in Figure 1 Also assess for evidence of liver failure

If cause not found, perform the tests shown in Figure 1, plus the following: • Antinuclear antibody • Ceruloplasmin • Hepatitis A IgM • Hepatitis B core IgM • INR • Serum Ig levels • Smooth muscle antibody

If above testing is unrevealing and/or there is evidence of liver failure, provide urgent referral to liver specialist and/or consider liver biopsy.

Figure 2. Moderate ALT elevation (5-15 × ULN).

ALT, alanine aminotransferase; IgM, immunoglobulin M; INR, international normalized ratio; ULN, upper limit of normal.

Adapted from reference 7.

History, physical exam, and assessment as in Figures 1 and 2

If cause not found, perform the tests shown in Figures 1 and 2, plus the following: • Anti-LKM • CMV serologies • EBV serologies • HSV serologies • Serum drug panel • Urine drug panel • Doppler ultrasound

Consider use of NAC with or without known history of acetaminophen use.

➞

emergent referral to a specialized liver center or liver transplant center.

Clinicians then need to consider the most common liver diagnoses and assess the pretest probability of finding a particular etiology for the abnormal liver tests. Depending on the patient population, the most common liver issues include fatty liver disease, alcoholic liver disease, viral hepatitis, and drug-induced liver injury. With fatty liver disease and alcoholic liver disease being so common and increasing in frequency, especially for patients with minimal or mild liver enzyme elevations, sometimes starting by just working on these risk factors and then reassessing liver tests a few months later is a reasonable first-line approach. In general, clues to the more prevalent diseases should be sought before searching for less common liver issues such as metabolic/genetic diseases, autoimmune diseases, or PBC and PSC. Patients with milder liver enzyme elevations generally will start with basic workup, such as viral hepatitis testing, iron panel/ferritin, and ultrasound. If unrevealing and the liver test abnormalities persist, then further evaluation can be done. On the other hand, patients with more significant elevations of liver enzymes at presentation should get more thorough evaluation earlier.

Liver damage can be broken down into 4 patterns of liver enzyme elevations: 1. hepatocellular (disproportionate elevation of AST/ALT); 2. cholestatic (disproportionate elevation of alkaline phosphatase); 3. mixed (elevation of AST/ALT and alkaline phosphatase); and 4. isolated hyperbilirubinemia.

Clinicians usually can just look at the lab tests to determine the pattern, or an R value can be calculated (>5, hepatocellular; 2-5, mixed; and <2, cholestatic).

Table 1 shows the usual AST to ALT elevation patterns seen in multiple liver diseases. In many liver diseases, as cirrhosis develops, ALT levels will decrease and AST levels will increase proportionately. Thus, many liver diseases that begin as ALT predominant, such as viral hepatitis, can eventually show a pattern of AST > ALT in the later cirrhotic phases. Because this fact is not

If above testing is unrevealing and/or there is evidence of liver failure, provide urgent referral to liver specialist or liver transplant center and/or consider liver biopsy.

Figure 3. Severe ALT elevation (>15 × ULN).

CMV, cytomegalovirus; EBV, Epstein-Barr virus; HSV, herpes simplex virus; LKM, liver-kidney microsomal; NAC, N-acetylcysteine; ULN, upper limit of normal.

Adapted from reference 7.

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always understood, many patients are accused of having active ongoing alcohol use as the cause of their AST > ALT liver test pattern. In addition, many patients have multiple underlying liver issues that can complicate the AST/ALT ratio.

Table 2 shows the usual magnitude of AST/ ALT elevations seen in various liver diseases.

These can help to define the etiology and determine the rapidity and type of workup necessary.

Again, patients can have a combination of liver diseases that can alter the magnitude, such as a patient with viral hepatitis and/or alcoholic liver disease who takes significant amounts of acetaminophen.

In the 2017 ACG guideline, using our proposed levels for true normal ULN as discussed above, we broke down the magnitude of ALT elevations into 5 categories: borderline (<2 × ULN), mild (2-5 × ULN), moderate (5-15 × ULN), severe (>15 × ULN), and massive (>10,000 IU/L).6 These various categories are discussed in the ALT algorithms (Figures 1-4).

Borderline and mild ALT elevations should be evaluated within a few months. Moderate, severe, and massive elevations should be evaluated immediately.

Clinicians also should try to define temporal

History, physical exam, and assessment as in Figures 1-3 Also assess for evidence of: • Ischemia • Rhabdomyolysis

➜ If cause not found, perform the tests shown in Figures 1-3.

➜ Consider use of NAC with or without known history of acetaminophen use.

Approach to Elevated ALT Because ALT is more liver specific than AST, the algorithms use ALT and are divided based on the magnitude of the elevations (Figures 1-4).

The initial extent and rapidity of the workup is based on the severity of the elevations. Higher ALT levels warrant more testing, including for uncommon causes of liver disease, at the initial visit. The guideline also suggests evaluation for signs of liver failure in patients with higher ALT levels. In addition, there is a lower threshold to consider liver biopsy in patients with more significant elevations. The use of N-acetylcysteine in patients with severe and massive elevations of ALT can be considered if there is suspicion of possible primary acetaminophen toxicity, acetaminophen toxicity on top of another liver etiology, or concern for impending liver failure even in the absence of known acetaminophen use.

➜

Approach to Elevated Alkaline Phosphatase

If unrevealing and/or evidence of liver failure, provide urgent referral to liver specialist or liver transplant center and/or consider liver biopsy.

Figure 4. Massive ALT elevation (>10,000 IU/L).

ALT, alanine aminotransferase; NAC, N-acetylcysteine.

Adapted from reference 7.

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relationships between potential liver insults and elevated liver enzymes. For example, although any medication theoretically can injure the liver, standardly, we would consider medications started more recently to be a more likely culprit.

In addition, similar consideration would need to be given to risk factors such as recent foreign travel, recent parenteral risk factors, and recent evidence of hypotension and other cardiovascular instability that might correlate with ischemic hepatitis or shock liver.

Liver biopsy often is believed to be the gold standard for determining the etiology of elevated liver enzymes, but there are many potential issues associated with liver biopsy, including risk, adverse events, cost, and hesitancy, from the patient’s standpoint. In addition, the biopsy report often is descriptive rather than diagnostic. These various factors should influence liver biopsy decisions.

Hepatology Insights

The elevated alkaline phosphatase algorithms start by determining whether it is likely a liver source or a nonhepatic source via assessment of other liver tests and/or using a clarifying test, such as GGT or alkaline phosphatase isoenzymes (Figures 5 and 6). In patients with otherwise normal liver tests, as shown in Figure 5, the first step

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Normal Search for nonliver sources

Check GGT

Abnormal

History and physical exam Assess for: • Potentially hepatotoxic medications ERCP or MRCP

Ultrasound shows ductal dilation Testing negative and alkaline phosphatase 1-2 × ULN

• • • •

AMA Antinuclear antibody Smooth muscle antibody Ultrasound AMA-positive

Repeat alkaline phosphatase in 3-6 mo Testing negative and alkaline phosphatase >2 × ULN

Evaluate for PBC

Alkaline phosphatase persistently abnormal

Consider liver biopsy

Figure 5. Elevated alkaline phosphatase with normal bilirubin/AST/ALT. ALT, alanine aminotransferase; AMA, antimitochondrial antibody; AST, aspartate aminotransferase; ERCP, endoscopic retrograde cholangiopancreatography; GGT, gamma-glutamyl transferase; MRCP, magnetic resonance cholangiopancreatography; PBC, primary biliary cholangitis; ULN, upper limit of normal.

Adapted from reference 7.

would be the clarifying test and then proceeding with the workup if the cause is related to the liver.

However, in patients with other abnormal liver tests (Figure 6), the elevated alkaline phosphatase is assumed to be from a liver source, and the workup is started without clarifying tests.

Approach to Elevated Direct Bilirubin The first step with elevated bilirubin is fractionation of the bilirubin to determine whether it is unconjugated (indirect) or conjugated (direct) (Figure 7). For elevated unconjugated (indirect) bilirubin, the approach is to look for causes of

elevations not related to liver disease (classically Gilbert’s syndrome or hemolysis or occasionally medications). Usually, if the indirect bilirubin levels are mildly elevated and there is no other evidence of an obvious etiology, a presumptive diagnosis of Gilbert’s syndrome can be made, with no further follow-up necessary. However, if the elevations persist and are unexplained, symptomatic, worsening, and/or associated with abnormal ALT, then further workup could be considered. Figure 7 demonstrates the algorithm for elevated conjugated (direct) bilirubin. This workup is similar to that for patients with elevated alkaline phosphatase.

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History and physical exam Assess for: • Potentially hepatotoxic medications

Ultrasound shows ductal dilation Ultrasound

ERCP or MRCP

Ultrasound shows no ductal dilation

Testing negative and alkaline phosphatase 1-2 × ULN

Assess for: • AMA • Antinuclear antibody • Smooth muscle antibody

AMA-positive Evaluate for PBC

Repeat alkaline phosphatase in 3-6 mo AMA-negative and alkaline phosphatase >2 × ULN

Alkaline phosphatase persistently abnormal

Consider liver biopsy or MRCP Figure 6. Elevated alkaline phosphatase with elevated bilirubin/AST/ALT. ALT, alanine aminotransferase; AMA, antimitochondrial antibody; AST, aspartate aminotransferase; ERCP, endoscopic retrograde cholangiopancreatography; MRCP, magnetic resonance cholangiopancreatography; PBC, primary biliary cholangitis; ULN, upper limit of normal.

Adapted from reference 7.

Conclusion Elevated liver enzymes are a common consult for gastroenterology providers. The true healthy ULN for ALT should likely be much lower than that proposed by the standard reference lab, with levels of 29 to 33 IU/L and 19 to 25 IU/L defining a true healthy normal for men and women, respectively. Clinicians should focus on history, including all medications, herbal supplements, and over-the-counter preparations, and physical examination to point toward any obvious clues to the etiology of the elevations and rule out

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advanced liver disease and/or evidence of liver failure. Clinicians should consider the pretest probability of a particular liver disease. They also should use the pattern, magnitude, and timing of liver enzyme elevations to help define the most likely etiology. Liver biopsy should be reserved for cases with unclear etiology.

Finally, patients with significantly elevated liver enzymes and/or potential liver failure should be considered for early referral to a specialized liver center or liver transplant centers.

2024

History and physical examination Assess AST, ALT, alkaline phosphatase Review medications Look for potential etiologies: • Alcoholic hepatitis • Biliary obstruction • Cirrhosis • ICU jaundice • Post-op jaundice • Sepsis

Ultrasound shows ductal dilation Ultrasound

ERCP or MRCP

Ultrasound shows no ductal dilation Assess for: • AMA • Antinuclear antibody • Smooth muscle antibody

Testing negative and bilirubin persistently abnormal

Consider liver biopsy Figure 7. Elevated conjugated (direct) bilirubin.

ALT, alanine aminotransferase; AMA, antimitochondrial antibody; AST, aspartate aminotransferase; ERCP, endoscopic retrograde cholangiopancreatograpy; MRCP, magnetic resonance cholangiopancreatography.

Adapted from reference 7.

References 1.

Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J Med. 2000;342(17):1266-1271.

2.

Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol.

2003;98(5):960-967.

3.

Arndt V, Brenner H, Rothenbacher D, et al. Elevated liver enzyme activity in construction workers: prevalence and impact on early retirement and allcause mortality. Int Arch Occup Environ Health. 1998;71(6):405-412.

4.

Kim HC, Nam CM, Jee SH, et al. Normal serum aminotransferase concentration and risk of mortality from liver diseases: prospective cohort study.

BMJ. 2004;328(7446):983.

5.

Lee TH, Kim WR, Benson JT, et al. Serum aminotransferase activity and mortality risk in a United States community. Hepatology. 2008;47(3):880-887.

6.

Ruhl CE, Everhart JE. Elevated serum alanine aminotransferase and gamma-glutamyltransferase and mortality in the United States population.

Gastroenterology. 2009;136(2):477-485.

7.

Kwo PY, Cohen SM, Lim JK. ACG Clinical Guideline: evaluation of abnormal liver chemistries. Am J Gastroenterol. 2017;112(1):18-35.

8.

Ruhl CE, Everhart JE. Upper limits of normal for alanine aminotransferase activity in the United States population. Hepatology. 2012;55(2):447-454.

9.

Owens D, Evans J. Population studies on Gilbert’s syndrome. J Med Genet.

1975;12(2):152.

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2024

Study Underscores Need to Evaluate For Liver Disease in Patients With C. diff atients with Clostridioides difficile

P

infections who also have metabolic-

associated steatohepatitis are at increased risk for death and other severe complications, according to a retrospective study drawn from the National Inpatient Sample.

The investigators, from Rutgers-Robert Wood Johnson Medical School, in New Brunswick, N.J., noted that there is evidence that metabolicdysfunction–associated steatotic liver disease (MASLD) or metabolic-dysfunction–associated steatohepatitis (MASH) can lead to inflammation and increased infection risk, possibly as a result of impaired function of liver macrophages,

a diagnosis of MASLD and CDI between 2015 and 2017. The patients’ mean age was 66 years and 42.42% were female.

The researchers found that patients with CDI and MASH had a higher mean Charlson Comorbidity Index score (6.33) than patients with CDI only (5.12) or CDI and MASLD (3.40) (P<0.001). Mortality was higher in the CDI plus MASH cohort, at 7.11%, versus 2.1% for CDI plus MASLD and 6.36% for CDI alone.

Liver-related complications also were higher in the CDI plus MASH group than in those with CDI only and MASLD plus CDI (Table).

When a physician has a C. difficile patient with metabolic risk factors, it’s very important ... to consider the potential for underlying [MASH] and risk-stratify with noninvasive tools to define the presence or Some ‘Holes’ in the Data absence of advanced hepatic fibrosis or cirrhosis.

‘

’

—Manal Abdelmalek, MD Mayo Clinic, Rochester, Minn.

which are the first immune cells to process antigens and pathogens in the gastrointestinal tract.

Gut microbiome alterations in MASLD or MASH also may contribute to greater risk for C. difficile infection (CDI) and severity.

The study included records from 745,475 patients with a diagnosis of CDI only, 4,366 with a diagnosis of MASH and CDI, and 11,335 with

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Hepatology Insights

Commenting on the findings in an interview with GEN Priority Report, Sahil Khanna, MBBS, expressed some surprise at the lower mortality risk among patients with MASLD plus CDI than those with CDI. “I don’t know if I can make biological sense out of it,” said Dr. Khanna, who leads the clinical and research program at Mayo Clinic in Rochester, Minn., involving fecal microbiota transplantation for CDI. Noting that the study did not control for comorbid conditions, Dr. Khanna said, “I think there’s a lot of holes in this data before we start telling

2024

Table. Rates of Liver-Related Complications Across Patient Groups Complication

CDI plus MASH

CDI only

CDI plus MASLD

Liver failure,%

23.94

2.22

3.84

Liver cancer, %

3.21

0.40

0.31

Acute kidney injury, %

34.1

28.3

20.5

Septic shock, %

12.4

10.2

1.9

P value

Manal Abdelmalek, MD <0.001

people that if you get C. difficile in the hospital, you’re twice as likely to die if you have [MASLD].”

Manal Abdelmalek, MD, who also was asked to comment on the study, said the investigators used ICD-10 codes, which may not accurately stratify MASLD from MASH or define the severity of underlying liver disease. But she acknowledged that patients with fatty liver disease and particularly those with advanced hepatic fibrosis and cirrhosis are at increased risk for infections and poor clinical outcomes related to bacterial infections.

“It is unclear whether the increased mortality in patients with C. difficile and [MASH] is attributable to the presence of chronic liver disease or associated complications of metabolic syndrome.”

In particular, diabetes is a source of concern, according to Dr. Abdelmalek, the director of the NAFLD Clinical Research Program at Mayo Clinic in Rochester. “The prevalence of [MASH] among patients with type 2 diabetes is more than twofold higher than in the general population. Diabetes mellitus is a strong predictor for hepatic fibrosis in patients with [MASH].

In this analysis, we don’t know if diabetes was a confounding factor. Patients with diabetes may have slower gastrointestinal motility; impaired wound healing response; and they may have

hyperglycemia, which can increase morbidity and mortality from C. difficile and other bacterial infections,” she said.

However, Dr. Khanna said if the study’s findings are confirmed, they would further underline the need to manage MASLD to reduce hepatitis.

Just as important as identifying CDI in patients with MASH, Dr. Abdelmalek stressed that when a physician has a C. difficile patient with metabolic risk factors, “it’s very important … to consider the potential for underlying [MASH] and risk-stratify with noninvasive tools to define the presence or absence of advanced hepatic fibrosis or cirrhosis, because patients with undiagnosed and unrecognized cirrhosis can more readily get into trouble from C. difficile infection. It gets to the issue of early diagnosis and recognition of liver disease, which sometimes falls below the radar screen.” In addition, she said, chronic liver disease and obesity and associated metabolic syndrome are linked to higher use of the healthcare system and heightened hospitalization risk, and, in turn, the potential for higher risk for C. difficile exposure.

—Jim Kling Dr. Abdelmalek reported a financial relationship with Intercept. Dr. Khanna reported financial relationships with Finch, Immuron, Niche, Pfizer, Probiotech, Rebiotix/Ferring, Seres, Takeda and Vedanta.

Hepatology Insights

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2024

Easing ALP Cutoffs Could Allow More With PBC to Benefit From New Therapies

P

atients with primary biliary cholangitis who have alkaline phosphatase levels below 1.67

times the upper limit of normal may have clinical

Eligibility for second-line treatment is based on alkaline phosphatase (ALP) levels above 1.67 times the upper limit of normal (ULN), treated with second-line therapy, according to a but there is a linear increase in risk with rising study presented at EASL Congress 2023.

ALP levels, according to Gideon Hirschfield, MD, who presented the research (abstract WED-256). “Biology is not black and white, and cutoffs are artificial and only as good as the data. What about that ALP level could be combined with other measures such as ELF score population of patients between alkaline phosor transient elastography to provide confidence that treatment to phatase elevated and 1.67 who currently would normal ALP levels would be advantageous for patients.

—Zobair M. Younossi, MD not be reimbursable for Inova Fairfax Medical Campus, Falls Church, Va. second-line treatment and who might benefit from these new potent, better treatments,” said Dr. Hirschfield, the chair of autoimmune liver

characteristics suggesting that they should be

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Hepatology Insights

2024

disease research at Toronto Centre for Liver Disease.

The study, which used data from previously conducted clinical trials of ursodeoxycholic acid as first-line therapy for the condition, examined data from 1,111 patients in 27 countries.

Overall, 284 patients had ALP levels above normal but below the cutoff of 1.67 required for trial entry. Among them, 42.0% had bilirubin levels greater than 0.6 x ULN, compared with 51.1% of patients who qualified for the trial; 27.2% had Enhanced Liver Fibrosis (ELF) scores of at least 10 versus 43.2%. The patients not meeting the cutoff also frequently had higher than ULN levels of alanine aminotransferase (19.1%) and aspartate aminotransferase (24.0%). GLOBE score was greater than 0.3 in 33.8% and gamma-glutamyl transferase was at least 3.2 ULN in 34.6%.

The new study suggested more patients should be considered as candidates for the newer therapies. “What we find is that this cohort of patients, in fact, do have clinical risk factors for disease progression. Many of these patients had liver fibrosis as per the ELF score or had markers of disease characteristics that are associated with worse outcomes.

Therefore, this group of patients is not being best served necessarily by not being given the chance to have new drugs,” Dr. Hirschfield said.

CymaBay, the manufacturer of seladelpar, an investigative peroxisome proliferator-activated receptor (PPAR)-delta agonist, announced in September that it intends to launch a phase 3b/4 trial with expanded criteria to include this patient population. That follows data from the ENHANCE phase 3 clinical trial showing a benefit (Hepatology 2023;78[2]:397-415).

“If drugs like seladelpar and others are going to be developed, we should be very proactive in trying to get those delivered to the largest number of patients at risk, not the least number of patients at risk,” Dr. Hirschfield said.

Others agree. “We’ve thought it would be ideal to treat patients to a normal alkaline phosphatase, but we’ve never really had the power to

do it in patients not fully responsive to approved treatments,” Gautham Reddy, MD, an associate professor of medicine at The University of Chicago Medicine, who was not involved in the research, told GEN Priority Report. “With this new generation of drugs that are coming out, [such as] the PPAR drugs, I think we’re going to have a lot more ability to try to normalize alkaline phosphatase. I think it’s where the field is moving towards, and we’ll start to see some more robust [clinical outcome] data in the next few years.”

‘ Biology is not black and white, and cutoffs are artificial and only as good as the data.’

—Gideon Hirschfield, MD Toronto Centre for Liver Disease

It would be even better to have multiple outcome measures, according to Zobair M. Younossi, MD, who also was not involved in the study. ALP level could be combined with other measures such as ELF score or transient elastography to provide confidence that treatment to normal ALP levels would be advantageous for patients, said Dr. Younossi, a professor of medicine at Inova Fairfax Medical Campus in Falls Church, Va. “If all of them go in the same direction, that will ultimately lead probably to improvement of scarring of the liver or fibrosis progression. In that context, I think I would remain optimistic that if we have drugs that can completely normalize alkaline phosphatase, that could translate into clinical benefit in the long run.”

—Jim Kling Dr. Hirschfield reported financial relationships with CymaBay, Escient, Gilead, GlaxoSmithKline, Intercept, Ipsen, Mirum and Pliant. Dr. Reddy was a site primary investigator for a clinical trial with CymaBay.

Hepatology Insights

33

2024

Disappointing Results for U.S. Hepatitis C Clearance Cascade nly 34% of people with diagnosed hepatitis C virus (HCV) in the United States have achieved viral clearance, according to data from 2013 to 2022.

O

This finding means progress is lagging far behind goals set by the Viral Hepatitis National Strategic Plan for the nation, which calls for at least 80% of people with HCV to achieve viral clearance by 2030 (MMWR Morb Mortal Wkly Rep 2023;72:716-720).

“The findings are incredibly concerning,” Carolyn Wester, MD, the director of the Division of Viral Hepatitis in the CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, said in an interview.

“There are over 2 million people living with hepatitis C in the U.S.,” Dr. Wester said. “It’s a silent killer. ...most people don’t know they have symptoms until they have advanced disease.

Fortunately, breakthrough cures have become available over the last decade.”

The report analyzed data from a large commercial laboratory, focused on a total of 1,719,493 people who were identified as having HCV from Jan. 1, 2013 through Dec. 31, 2021—the decade since highly effective direct-acting antiviral hepatitis C treatments became available. Data came from all 50 states and the District of Columbia.

During the decade, 88% of infected people were classified as having received viral testing. Among those who received viral testing, 69% were classified as having initial infection.

Of that group, 34% were classified as cured or cleared; and of those patients, 7% were categorized as having persistent infection or reinfection.

“After a decade of having a breakthrough cure, only one out of three people diagnosed with hepatitis C has actually been cured,” Dr. Wester said, noting that this is “just part of the story.”

“We know that upstream of that, an estimated 40% of people with hepatitis C aren’t even diagnosed,” she added.

Viral clearance was lowest in people 20 to 39 years of age (24%), and individuals with other, unspecified or Medicaid insurance had lower viral clearance (23%, 33% and 31%, respectively) than those with Medicare and commercial insurance

34

(40% and 45%, respectively).

Factors Preventing Treatment “We know that there are a lot of factors inhibiting the ability of people with hepatitis C to get linked to curative treatment, but even among those who are diagnosed, some of the factors include the high cost of treatment, insurance restrictions, and the fact that treatment isn’t available in many of the settings where people with hepatitis C receive care,” Dr. Wester said.

Primary care settings may not offer HCV treatment services, she said. In addition, many individuals are not receiving care via longitudinal primary care settings and instead access services at syringe service programs, substance abuse disorder treatment clinics, correctional facilities or emergency departments. “Those settings might be set up to diagnose but not to treat,” Dr. Wester said.

Furthermore, while the high cost of care has come down, it is still cost-prohibitive for many people, with or without insurance.

Barriers Need to Be Addressed Dr. Wester stressed that the results of the study highlight that action must be taken promptly to address the multiple barriers that are preventing people with HCV from receiving services and achieving viral clearance.

“Even the groups that did the best—individuals 60 and older with commercial or Medicare insurance—still only had evidence of viral clearance at 48%,” she said.

“There is a big opportunity, but a big problem as well,” Dr. Wester added. “Right now, we need a big solution. The Biden-Harris administration has proposed a national hepatitis C elimination program, which would provide for rapid diagnosis, affordable treatment, and access to testing and cure in a variety of settings where people receive care. We can’t wait another 10 years. Everyone with hepatitis C deserves to be cured.”

Hepatology Insights

—Ethan Covey

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